A process for the production of a crystalline form of atazanavir sulfate

Abstract

This invention discloses a method for producing atazanavir sulfate crystal form, comprising the following steps: with or without inert gas protection, reacting atazanavir with sulfuric acid in ethanol, adding n-heptane, crystallizing, separating, and drying to obtain atazanavir sulfate crystal form; wherein the amount of ethanol used is 3.5 to 15 times the weight of atazanavir, and / or the amount of n-heptane used is 2.5 to 12 times the weight of atazanavir. This method can conveniently control the crystal form of the obtained product, atazanavir sulfate, and compared with the prior art, greatly improves the convenience of production, operation, and / or control, is more conducive to industrial production, and significantly improves the accessibility of atazanavir sulfate crystal form drug, especially atazanavir sulfate crystal form A.

Description

Technical Field

[0001] This invention belongs to the field of crystalline drugs, specifically relating to a method for producing atazanavir sulfate crystalline form. Background Technology

[0002] AIDS, also known as Acquired Immunodeficiency Syndrome, is an immunodeficiency disease caused by the specific infection and killing of major lymphocytes by the human immunodeficiency virus (HIV). After infection, individuals are susceptible to opportunistic infections and malignant tumors due to the destruction of their immune system, resulting in a high mortality rate. Currently, there are no drugs or methods to completely cure it (see: Bai Yuefei, Liu Ju, Zhou Hong, et al. Research progress on the synthesis of raw materials for the HIV protease inhibitor atazanavir sulfate: Chinese Journal of New Drugs, 2018, Vol. 27, No. 7: 767-780).

[0003] Currently, HIV-infected individuals are primarily treated with drugs such as HIV protease inhibitors, reverse transcriptase inhibitors, and integrase inhibitors to improve their quality of life and life expectancy. Atazanavir is one such drug developed in the early 21st century. Because atazanavir sulfate has higher oral bioavailability in animals than its free base (i.e., atazanavir) and better water solubility and stability than other salts, it is often administered in the form of atazanavir sulfate in practical applications.

[0004] Atazanavir sulfate, also known as atazanavir sulfate or atazanavir hydrogen sulfate, has the chemical name (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(benzyl)-6-[[4-(2-pyrimidinyl)phenyl]methyl]-2,5,6,10,13-pentazatetradecanoic acid dimethyl ester hydrogen sulfate, with the molecular formula: C 38 H 52 N6O7·H2SO4 has the following structural formula:

[0005]

[0006] Because of its strong efficacy, it can continuously and effectively inhibit the HIV virus, and has the advantages of low drug resistance, convenient administration, and few adverse reactions, it has gradually become the most promising first-line drug for the treatment of AIDS at present.

[0007] Existing literature reports that atazanavir sulfate exists in multiple crystal forms, including hydrates and solvates, mainly type I (hereinafter referred to as type A or crystal form A), type II, type C (also known as C mode), type E3, and type H1. Among them, type A is an anhydrous, non-solventized crystal form, type II is a hydrated hygroscopic crystal form, type C is a hydrated crystal form, and type E3 is a triethanolic solvate crystal form.

[0008] Among these known crystal forms, crystal form A is a relatively important form and has attracted considerable attention. The original developer, Bristol-Myers Squibb Holding Ireland Limited, prepared atazanavir sulfate crystal form A using the following method: A free alkaline solution of atazanavir was reacted with concentrated sulfuric acid, the amount of concentrated sulfuric acid being less than approximately 15% by weight of the free alkaline solution. Atazanavir sulfate type A seed crystals were then added to the reaction mixture. As the bisulfate crystals formed, additional concentrated sulfuric acid was added in multiple stages at an increasing rate according to a cubic equation (also known as: tertiary crystallization technique or modified tertiary crystallization technique), ultimately resulting in the effective formation of atazanavir bisulfate type A crystals. However, if ethanol is used as the reaction solvent and heptane as the crystallization solvent, atazanavir sulfate E3 type is typically obtained: a triethanolamine solvate (see: CN1980666A and CN101565398A).

[0009] Because the original method requires a cubic equation with multiple stages and increasing rate of sulfuric acid addition, the operation is cumbersome and demanding, and difficult to control, which is not conducive to industrial production.

[0010] To address this technical problem, CN 105859611 A provides an improved method for preparing atazanavir hydrogen sulfate type A crystals. The specific steps are as follows: a) Place the free atazanavir base in ethanol, stir at room temperature, then add concentrated sulfuric acid dropwise, heat and stir the reaction mixture, add an inert solvent, cool to crystallize, filter, and dry to obtain atazanavir ethanolate type E crystals; b) Place the atazanavir ethanolate type E crystals obtained in step a) in acetone, heat under reflux with stirring, cool, filter, and dry to obtain atazanavir hydrogen sulfate type A crystals.

[0011] In other words, the method described in CN 105859611 A involves first reacting the free base of atazanavir with sulfuric acid in ethanol to obtain atazanavir ethanolate E-type crystals, and then performing a crystallization transformation to finally obtain atazanavir hydrogen sulfate A-type crystals. Although this method is an improvement over the original method, it is still somewhat cumbersome: it requires first preparing atazanavir ethanolate E-type crystals, and then performing a crystallization transformation to finally obtain atazanavir sulfate A-type crystals, which is not very conducive to industrial production.

[0012] In view of this, the present invention is hereby proposed. Summary of the Invention

[0013] To address the problems and / or shortcomings of existing technologies, the present invention aims to provide a method for producing atazanavir sulfate crystal form. This method allows for convenient control of the crystal form of the resulting atazanavir sulfate product. Compared with existing technologies, it significantly improves the convenience of production, operation, and / or control, making it more suitable for industrial production and significantly enhancing the accessibility of atazanavir sulfate crystal form drug, especially atazanavir sulfate crystal form A.

[0014] The present invention provides a method for producing atazanavir sulfate crystal form, which includes the following steps: with or without the use of an inert gas protection, atazanavir reacts with sulfuric acid in ethanol, then n-heptane is added, crystallization is performed, separation is carried out, and drying is performed to obtain atazanavir sulfate crystal form;

[0015] The amount of ethanol used is 3.5 to 15 times the weight of atazanavir, and / or the amount of n-heptane used is 2.5 to 12 times the weight of atazanavir.

[0016] Furthermore,

[0017] When the crystal form of atazanavir sulfate is atazanavir sulfate crystal form A, the amount of ethanol used is 6.4 to 6.8 times the weight of atazanavir, and / or the amount of n-heptane used is 5.8 to 6.2 times the weight of atazanavir.

[0018] Furthermore,

[0019] When the crystal form of atazanavir sulfate is atazanavir sulfate crystal form A, the amount of ethanol used is 6.6 times the weight of atazanavir, and / or the amount of n-heptane used is 6 times the weight of atazanavir.

[0020] Furthermore,

[0021] When the atazanavir sulfate crystal form is atazanavir sulfate crystal form A, the weight ratio of ethanol to n-heptane is 1:0.88 to 0.95; preferably, the weight ratio of ethanol to n-heptane is 1:0.9 to 0.92.

[0022] Furthermore,

[0023] When the atazanavir sulfate crystal form is atazanavir sulfate crystal form A, the reaction temperature is 10-30℃, and / or the crystallization temperature is 10-30℃; preferably, the reaction temperature is 25℃±2℃, and / or the crystallization temperature is 25℃±2℃.

[0024] Furthermore,

[0025] When the atazanavir sulfate crystal form is atazanavir sulfate crystal form E3, the amount of ethanol used is 3.6 to 4 times the weight of atazanavir, and / or the amount of n-heptane used is 2.5 to 3.2 times the weight of atazanavir; preferably, the amount of ethanol used is 3.8 times the weight of atazanavir, and / or the amount of n-heptane used is 3 times the weight of atazanavir.

[0026] Furthermore,

[0027] When the atazanavir sulfate crystal form is atazanavir sulfate crystal form E3, the weight ratio of ethanol to n-heptane is 1:0.7 to 0.8; preferably, the weight ratio of ethanol to n-heptane is 1:0.78 to 0.8.

[0028] Furthermore,

[0029] When the atazanavir sulfate crystal form is atazanavir sulfate crystal form E3, the reaction temperature is 32-40℃, and / or the crystallization temperature is 32-40℃; preferably, the reaction temperature is 35℃±2℃, and / or the crystallization temperature is 35℃±2℃.

[0030] Furthermore,

[0031] In any of the above-described methods for producing atazanavir sulfate crystals, the molar ratio of atazanavir to sulfuric acid is 1:1 to 1.5, and / or the crystallization time is 15 to 30 hours; preferably, the molar ratio of atazanavir to sulfuric acid is 1:1.08 to 1.12, and / or the crystallization time is 18 to 24 hours.

[0032] The present invention also provides a method for producing atazanavir sulfate crystal form H1, characterized in that it includes the following steps: obtaining atazanavir sulfate crystal form A or atazanavir sulfate crystal form E3 according to any of the above-described methods for producing atazanavir sulfate crystal forms, and then performing crystal transformation according to a known method to obtain atazanavir sulfate crystal form H1.

[0033] The beneficial effects of this invention are as follows: This invention takes a novel approach and, by employing a completely different technical means from existing technologies—adjusting the amount and ratio of the reaction solvent (ethanol) and the crystallization solvent (n-heptane)—it was unexpectedly discovered that this method can conveniently control the crystal form of the obtained product, atazanavir sulfate, greatly improving the convenience of production, operation, and / or control. This makes it easier and more convenient to obtain crystal form A of atazanavir sulfate, which is also more conducive to industrial production, significantly improving the accessibility of atazanavir sulfate crystal form drugs, and thus continuously contributing to the sustainable and healthy development of my country's pharmaceutical industry.

[0034] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention. Attached Figure Description

[0035] Figure 1 The image shows the X-ray powder diffraction (XRD) pattern of the product obtained in Example 3.

[0036] Figure 2 The image shows the X-ray powder diffraction (XRD) pattern of the product obtained in Example 8. Detailed Implementation

[0037] The present invention will be clearly and completely described below with reference to specific embodiments. Those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as a limitation on the scope of protection of the present invention.

[0038] In this invention, unless otherwise specified, the conditions shall be performed according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0039] Regarding the definitions of terms used in this invention, unless otherwise stated, the initial definitions provided herein apply to the term throughout the text; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and / or context.

[0040] Example 1

[0041] Under nitrogen protection, 30 kg (approximately 42.56 mol) of atazanavir and 100 kg of anhydrous ethanol were added to a reactor and stirred until homogeneous. Then, 4.8 kg of concentrated sulfuric acid (containing approximately 46.5 mol of H₂SO₄) was added, and the system temperature was controlled at 35℃±2℃. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with 14 kg of anhydrous ethanol. 90 kg of n-heptane was added to the filtrate, and the mixture was stirred at 35℃±2℃ for 20 hours to induce crystallization. After centrifugation, the filter cake was washed with a mixed solvent of anhydrous ethanol and n-heptane (mass ratio 1:0.9), and dried under vacuum (vacuum degree ≤ -0.09 MPa) to obtain atazanavir sulfate crystal form E3 (triethanol solvate), with an HPLC purity of 99.5%, a maximum single impurity of 0.31%, and a yield of 82.38%. XRD analysis showed that the XRD pattern of the obtained product was essentially the same as that of CN. The characteristic peaks of crystal form E3 described in 1980666A (Invention title: Method and new form for preparing atazanavir hydrogen sulfate, application date: May 3, 2005) are consistent.

[0042] Example 2

[0043] Under nitrogen protection, 30 kg (approximately 42.56 mol) of atazanavir and 350 kg of anhydrous ethanol were added to the reactor and stirred until homogeneous. Then, 4.8 kg of concentrated sulfuric acid (containing approximately 46.5 mol of H2SO4) was added, and the system temperature was controlled at 35℃±2℃. The mixture was stirred for 2 h, filtered, and the filter cake was washed with 25 kg of anhydrous ethanol. The resulting filtrate was stirred at 35℃±2℃ to crystallize for 20 h. After centrifugation, the filter cake was washed with anhydrous ethanol and dried under vacuum (vacuum degree ≤ -0.09 MPa) to obtain atazanavir sulfate crystal form E3 (triethanol solvate). XRD analysis showed that the XRD pattern of the obtained product was basically consistent with the characteristic peaks of crystal form E3 recorded in CN 1980666A.

[0044] Example 3

[0045] Under nitrogen protection, 30 kg (approximately 42.56 mol) of atazanavir and 178 kg of anhydrous ethanol were added to a reaction vessel and stirred until homogeneous. Then, 4.84 kg of concentrated sulfuric acid (containing approximately 46.88 mol of H₂SO₄) was added, and the system temperature was controlled at 25℃±2℃. The mixture was stirred for 2 h, filtered, and the filter cake was washed with 20 kg of anhydrous ethanol. 180 kg of n-heptane was added to the filtrate, and the mixture was stirred at 25℃±2℃ for 20 h to induce crystallization. After centrifugation, the filter cake was washed with a mixed solvent of anhydrous ethanol and n-heptane (mass ratio 1:0.9), and dried under vacuum (vacuum degree ≤ -0.09 MPa) to obtain atazanavir sulfate, a white solid with an HPLC purity of 99.89%, a maximum single impurity of 0.05%, and a yield of 84.55%.

[0046] IR results showed that the infrared absorption spectrum of the obtained product was consistent with the main characteristic absorption peaks of the infrared absorption spectrum of atazanavir sulfate standard; HPLC results showed that the retention time of the main peak of the obtained product was consistent with the retention time of the main peak of the standard.

[0047] The obtained product was analyzed by X-ray powder diffraction (XRD) under the following conditions:

[0048] Equipment model: Bruker D8 Advance (Germany); Cu (40kV, 40mA); Wavelength for calculating lattice spacing d = (Cu / K-alphal).

[0049] The test results are shown in Table 1 and Figure 1 .

[0050] Table 1. X-ray powder diffraction (XRD) results of the products obtained in Example 3.

[0051]

[0052] XRD results showed that the obtained product, atazanavir sulfate, had characteristic peaks at diffraction angles of 2θ = 6.02, 9.08, 9.90, 11.72, 18.22, and 18.67 (±0.2) degrees, which were consistent with the characteristic peaks of crystal form A recorded in CN 1980666A, thus confirming that the product obtained in Example 3 was crystal form A of atazanavir sulfate.

[0053] Example 4

[0054] The same content as in Example 3 will not be repeated. The difference is that the amount of concentrated sulfuric acid used is changed to 4.4 kg (containing approximately 42.62 mol of H2SO4), that is, the molar ratio of atazanavir to sulfuric acid (H2SO4) is 1:1. Atazanavir sulfate is then prepared under the same process conditions with an HPLC purity of 98.56% and a yield of 77.5%. XRD analysis shows that the XRD pattern of the obtained product is basically consistent with the characteristic peaks of crystal form A recorded in CN 1980666A.

[0055] Example 5

[0056] The same content as in Example 3 will not be repeated. The difference is that the amount of concentrated sulfuric acid used is changed to 5.28 kg (containing approximately 51.14 mol of H2SO4), that is, the molar ratio of atazanavir to H2SO4 is 1:1.2. Atazanavir sulfate is then prepared under the same process conditions with an HPLC purity of 99.92% and a yield of 69.7%. XRD analysis shows that the XRD pattern of the obtained product is basically consistent with the characteristic peaks of crystal form A recorded in CN1980666A.

[0057] Example 6

[0058] The same content as in Example 3 will not be repeated. The difference is that the stirring and crystallization time was adjusted from 20h to 23h, and then atazanavir sulfate was prepared under the same process conditions with an HPLC purity of 99.85% and a yield of 82.38%. The XRD pattern of the obtained product was basically consistent with the characteristic peaks of crystal form A recorded in CN 1980666A.

[0059] Example 7

[0060] Using the atazanavir sulfate crystal form E3 (triethanol solvate) obtained in Example 1 as raw material, crystal transformation was performed according to the known method disclosed in patent CN107382833A (e.g., Example 8) to obtain atazanavir sulfate crystal form H1.

[0061] Example 8

[0062] Using the atazanavir sulfate crystal form A obtained in Example 3 as raw material, the product was transformed into crystal form H1 by following the known method disclosed in patent CN 107382833 A (e.g., Example 5). The XRD results are shown in Table 2. Figure 2 .

[0063] Table 2. X-ray powder diffraction (XRD) results of the product obtained in Example 8

[0064]

[0065] also,

[0066] The research and production practice of this invention have also revealed that, consistent with relevant reports in the prior art, using ethanol as the reaction solvent and heptane as the crystallization solvent, in most cases, the product obtained is atazanavir sulfate crystal form E3 (triethanol solvate) or mixed crystals. Only under specific dosage and ratio conditions within a narrow range is the product obtained as atazanavir sulfate crystal form A. Moreover, the crystallization temperature has a significant impact on the crystal form of the obtained product. In the temperature range of 10 to 30°C, it is advantageous for the obtained product to be atazanavir sulfate crystal form A, while crystallization temperatures exceeding 30°C (e.g., 35°C ± 2°C) often result in atazanavir sulfate crystal form E3 (triethanol solvate) or mixed crystals.

[0067] Of course, the present invention can also have other various embodiments. Without departing from the spirit and essence of the present invention, those skilled in the art can make various corresponding changes and / or modifications according to the present invention, and these corresponding changes and / or modifications should all fall within the protection scope of the appended claims.

Claims

1. A process for the production of a crystalline form of atazanavir sulfate characterized by, It includes the following steps: Under nitrogen protection, 30 kg of atazanavir and 178 kg of anhydrous ethanol are added to a reaction vessel and stirred until homogeneous. Then, 4.84 kg of concentrated sulfuric acid is added, and the system temperature is controlled at 25℃±2℃. The mixture is stirred for 2 hours, filtered, and the filter cake is washed with 20 kg of anhydrous ethanol. 180 kg of n-heptane is added to the filtrate, and the mixture is stirred at 25℃±2℃ for 20 hours to induce crystallization. After centrifugation, the filter cake is washed with a mixed solvent of anhydrous ethanol and n-heptane at a mass ratio of 1:0.

9. The mixture is then vacuum dried with a vacuum degree ≤-0.09 MPa to obtain atazanavir sulfate crystal form A.

2. The production method according to claim 1, characterized by, The amount of concentrated sulfuric acid used was changed to 4.4 kg.

3. The production method according to claim 1, characterized by, The amount of concentrated sulfuric acid used has been changed to 5.28 kg.

4. The production method according to claim 1, characterized by, The stirring and crystallization time was adjusted from 20h to 23h.

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